Prognostic factors of epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitor (TKI): a nationwide registry study in China

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of all cases (1-3). Among patients with NSCLC, somatic mutations in the epidermal growth factor receptor (EGFR) gene are crucial molecular targets, particularly in adenocarcinoma, non-smokers, females, and individuals of Asian descent (4). The most common EGFR mutations—exon 19 deletions and exon 21 L858R point mutations—represent 85% to 90% of cases and are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs). As a result, EGFR-TKIs are considered the preferred first-line treatment, with clinical trials demonstrating improved objective response rates (ORR) and progression-free survival (PFS) compared with conventional chemotherapy (5-11).

Despite the proven efficacy of EGFR-TKIs, randomized controlled trials (RCTs) often fail to fully represent real-world patient populations. These trials typically enroll patients under idealized conditions, excluding those with comorbidities or extensive prior treatments. Consequently, their findings may not reflect the diversity of patients encountered in everyday clinical practice, highlighting the need for large-scale real-world studies to assess prognostic factors across a broader patient base.

However, many real-world studies are constrained by small sample sizes and insufficient follow-up periods, which can limit the generalizability and reliability of their findings. For example, Sakata et al.’s study, which included only 538 patients, focused on osimertinib as a first-line treatment but lacked the statistical power to fully evaluate prognostic factors (12). Similarly, a study of 237 patients treated with first- or second-generation EGFR-TKIs identified factors such as older age, poor performance status, primary metastatic disease, and synchronous brain metastases as independent predictors of poor prognosis, but was also limited by its small sample size and the inability to explore multivariate interactions comprehensively (13,14).

To address these limitations, “Meina Xinsheng”, a nationwide prospective registration platform, has recorded extensive data on icotinib usage across China. By linking this dataset to the national death registration database at the Chronic Disease Center of the China Center for Disease Control, we were able to conduct a comprehensive analysis of icotinib use in advanced lung cancer treatment. This study aims to provide robust, generalizable insights into prognostic factors in patients with advanced NSCLC treated with EGFR-TKIs in real-world settings, particularly those harboring EGFR mutations, thereby overcoming the constraints of previous small-scale studies. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-275/rc).

Methods

Data sources and patient inclusion

We used data from “Meina Xinsheng”, a nationwide registration platform managed by the China Pharmaceutical Innovation Promotion Association (http://www.phirda.com/, http://www.bettasjpt.com/), which has been actively maintained since November 2011. All registered patients received icotinib (Conmana^®), a first-generation EGFR-TKI approved by the China Food and Drug Administration in June 2011.

Patient enrollment began in November 2011, with registration occurring at the time of the first dose of icotinib. Data on the platform were validated by authorized medical practitioners and reviewed by support personnel. Patients eligible for inclusion had to meet the following criteria: (I) a pathological diagnosis of NSCLC at stage IIIb or IV, and (II) receipt of at least one dose of icotinib. Patients prescribed icotinib as adjuvant therapy were excluded. Eligible patients underwent chest computed tomography (CT) and brain magnetic resonance imaging (MRI) every 2 months, with tumor response assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients who were discharged continued to be monitored every 2 months for survival status via physician consultations or telephone follow-ups. EGFR mutation status was determined according to routine clinical practice at each participating center. In the vast majority of patients, EGFR testing was performed on tumor tissue samples obtained from biopsy or surgical specimens. In a minority of cases, plasma-based assays (liquid biopsy) were used when tumor tissue was unavailable or inadequate. Data collected for this study included baseline characteristics, medication use, efficacy assessments, and follow-up information through June 2022.

To minimize potential biases from loss to follow-up and ensure accurate survival measurement, we linked patient data with the National Death Registration Database of the Chronic Disease Center at the China Center for Disease Control. This database, part of a nationwide network, has been used since 2010 to monitor and report causes of death.

Study design

This retrospective cohort study aimed to identify prognostic factors in patients with advanced EGFR-mutated NSCLC treated with icotinib in routine clinical practice. The study was approved by the Ethics Committee of the Guangzhou National Center for Respiratory Medicine (No. ES-2022-197) and registered with the National Clinical Research Center for Respiratory Disease of China (No. ChNCRCRD-2022-GZ02). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. All patients provided written consent for their data to be used in scientific analysis at the time of registration.

The primary outcomes were overall survival (OS), duration of treatment (DoT), lung cancer-specific survival (LCSS), and the proportion of long-term survivors among patients with advanced NSCLC receiving icotinib. OS was defined as the time from the first dose of icotinib to death from any cause or last follow-up, and DoT as the time from icotinib initiation to permanent discontinuation for any reason, including disease progression, toxicity, or death. Long-term survival was defined as an OS duration of more than 5 years. LCSS was defined as the time from the first dose of icotinib to death recorded as being due to lung cancer in the national death registry. Prognostic factors evaluated included sex, age, Karnofsky Performance Status (KPS), disease stage, histology, mutation type, treatment line, and response type. Disease control was defined as achieving complete response (CR), partial response (PR), or stable disease (SD) according to RECIST. We explored the association between the duration of disease control and long-term survival and identified 22 months as the optimal cut-off using time-dependent ROC analysis. To ensure sufficient follow-up for survival outcomes and reduce bias from recent enrollees, we restricted the primary survival analyses to patients who initiated icotinib between January 1, 2012, and December 31, 2018.

Statistical analysis

Continuous variables were compared using the Student’s t-test, while categorical variables were compared using the Chi-squared test (15). The Kaplan-Meier method (16) and log-rank tests (17) were employed to estimate and compare median survival and treatment duration. A multivariable Cox proportional hazards regression model (18) was used to identify factors associated with survival. All statistical tests were two-sided, and P<0.05 was considered statistically significant. All analyses were conducted using SPSS version 23.0 (SPSS, Chicago, IL), and visualizations were created with Hiplot (https://hiplot.com.cn).

Results

Baseline patient characteristics

A total of 231,699 patients from 3,445 hospitals nationwide were registered for the use of icotinib (Figure 1). After excluding patients with incomplete pathological records (n=734), those with non-NSCLC cancers such as esophageal cancer, head and neck squamous cell carcinoma, and small cell carcinoma (n=76), and those who received the drug as postoperative adjuvant treatment (n=9,101), the final analysis included 221,788 patients with advanced NSCLC (Figure 2). The mean age of these patients was 62.6 years, and females accounted for a higher proportion of the cohort. The majority of patients had a KPS score between 80 and 90. Most patients had a KPS score between 80 and 90, and adenocarcinoma was the most common histological type. Among patients with documented EGFR mutation subtypes, exon 19 deletions and L858R mutations were observed at comparable frequencies (Table 1).

Figure 1 Case distribution in the “Meina Xinsheng” registry. Distribution of registered cases in the “Meina Xinsheng” nationwide registry of EGFR-TKI treatment. The figure illustrates the number of included patients by participating hospitals or regions, reflecting the geographic spread of EGFR-TKI use in routine clinical practice across China. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Figure 2 Flow chart of patient inclusion and analysis cohorts. Flow diagram showing patient selection from the “Meina Xinsheng” nationwide registry. Among all patients registered for EGFR-TKI therapy, those with advanced NSCLC were identified as the overall study population. A subset of patients treated between 2012 and 2018 with complete survival information constituted the 2012–2018 survival analysis cohort. Key exclusion criteria (e.g., non-NSCLC histology) and the final numbers included in each analytic cohort are shown at each step. CDC, Centers for Disease Control and Prevention; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

OS and treatment duration

Among the cohort, 83,791 patients who initiated icotinib treatment between 2012 and 2018 were included in the survival analysis, with 55,670 deaths reported. The median OS for this cohort was 3.2 years (95% CI: 3.18–3.3), and the median LCSS was 4.1 years (95% CI: 4.02–4.1) (Figure 3). The median DoT was 14.0 months (95% CI: 13.9–14.1).

Figure 3 OS and LCSS in the survival analysis cohort. Kaplan-Meier curves depicting OS and LCSS in the 2012–2018 survival analysis cohort of patients with advanced NSCLC treated with EGFR-TKIs. Median survival times with 95% CIs and survival probabilities at predefined time points (e.g., 1, 3, and 5 years) are indicated. Censoring is marked by tick marks on the curves. CI, confidence interval; EGFR, epidermal growth factor receptor; LCSS, lung cancer-specific survival; NSCLC, non-small cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Subgroup differences in survival and treatment duration

Subgroup analyses showed that longer OS and DoT were consistently observed in the following groups (Figure 4): females, patients with stage III lung cancer, those with adenocarcinoma histology, patients with EGFR exon 19 deletions, those with higher KPS scores, and those receiving icotinib as first-line treatment. Patients who achieved a CR had a median OS of 5 years (95% CI: 4.5–5.4), which was 1.6 years longer than those without CR (including lost-to-follow-up cases), although the difference in DoT was only 4 months. In contrast, patients with non-adenocarcinoma histology or non-sensitive mutations exhibited poorer prognoses. Discrepancies in trends were noted. For example, younger patients (age <40 years) demonstrated prolonged survival but shorter DoT. Patients with wild-type EGFR status, despite shorter DoT, showed better OS.

Figure 4 Subgroup analyses of overall survival and duration of treatment. Kaplan-Meier curves showing (A) OS and (B) DoT in the 2012–2018 survival analysis cohort, stratified by clinically relevant subgroups. Subgroups include sex, age category, disease stage, KPS score, histology, EGFR mutation subtype, treatment line, and efficacy evaluation. Numbers at risk for each subgroup are displayed below the x-axis. Median OS or DoT with 95% CIs are indicated for each subgroup. ADC, adenocarcinoma; ADSC, adeno-squamous carcinoma; CI, confidence interval; CR, complete response; DoT, duration of treatment; EGFR, epidermal growth factor receptor; KPS, Karnofsky Performance Status; LCC, large cell carcinoma; OS, overall survival; SQC, squamous cell carcinoma.

Long-term survivors and duration of disease control

The inclusion of non-mortality cases in the calculation of long-term survivors may introduce bias due to potential loss to follow-up. To obtain a more precise estimate, we therefore restricted this analysis to deceased patients. Of the 55,670 deaths, 7.7% (n=4,306) had survived for more than 5 years. Females, younger patients, those with stage IV disease, those receiving later-line treatment, and those who achieved CR were more likely to be long-term survivors (Figure 5). Patients who maintained disease control for at least 22 months had significantly higher long-term survival rates than those who did not (12.8% vs. 2.7%).

Figure 5 Proportion of long-term survivors in different subgroups. Bar plots showing the percentage of long-term survivors (overall survival >5 years) across predefined clinical and molecular subgroups in the 2012–2018 survival analysis cohort. Subgroups include age categories, sex, KPS score, histology, disease stage, treatment line, efficacy evaluation, and DoT. **, P<0.01; ***, P<0.001. ADC, adenocarcinoma; ADSC, adeno-squamous carcinoma; CR, complete response; DoT, duration of treatment; KPS, Karnofsky Performance Status; LCC, large cell carcinoma; ns, not significant; SQC, squamous cell carcinoma.

Multivariable analysis of prognostic factors for OS

Multivariable Cox regression analysis confirmed that several clinicopathologic features were independently associated with OS (Table 2). Concomitant EGFR 19del + L858R (vs. wild type) was associated with longer OS, and EGFR exon 19 deletion showed a favorable trend. In contrast, older age, squamous or adeno-squamous histology (vs. adenocarcinoma), non-EGFR mutation (vs. wild type), stage IV disease (vs. stage III), and the absence of CR were associated with worse OS, whereas sex, KPS score, and treatment line were not independently associated with OS after adjustment.

Discussion

This nationwide real-world study of icotinib treatment in advanced NSCLC provides robust evidence on survival outcomes and prognostic factors in a very large population of patients with EGFR-mutant disease. By leveraging a prospective registry linked to a national death database, we were able to characterize OS, long-term survival and treatment duration under routine clinical practice, and to identify a set of clinical, pathological and molecular factors associated with prognosis. These findings complement existing trial-based and real-world data while addressing the need for large-scale, population-based analyses in non-Western cohorts.

In our multivariable analysis, female sex, stage III (vs. stage IV) disease, adenocarcinoma histology, EGFR exon 19 deletion, and the use of EGFR-TKI as first-line therapy emerged as favorable prognostic factors. These associations are biologically and clinically plausible (19-21). Female patients with EGFR-mutant NSCLC often have a lower smoking burden, fewer comorbidities, and a higher prevalence of sensitizing EGFR mutations, all of which may contribute to better outcomes with EGFR-TKIs. Patients with stage III disease generally have a lower metastatic burden and less extensive organ involvement than those with stage IV disease, which may translate into longer survival even under systemic TKI treatment (22). Adenocarcinoma histology is the predominant context for EGFR mutations, and the biological phenotype of EGFR-mutant adenocarcinoma appears more strongly TKI-sensitive than non-adenocarcinoma histologies (23-27).

We also observed that patients with EGFR exon 19 deletions experienced better outcomes than those with other mutation patterns, consistent with previous studies showing that 19del is associated with higher response rates and longer survival than L858R (28,29). This may reflect differences in oncogenic signaling dependence and TKI sensitivity between mutation subtypes. Furthermore, initiating EGFR-TKI as first-line therapy allows maximal exploitation of EGFR-TKI sensitivity and avoids early chemotherapy-related toxicity or delay in targeted treatment, which together may contribute to longer DoT and OS. Our finding that CR was independently associated with improved survival underscores the importance of achieving deep responses in maximizing the long-term benefit of EGFR-TKIs.

Comparisons with reported cohorts highlighted both similarities and disparities (20,30,31). A study using the Netherlands Cancer Registry on 873 patients reported a median OS of 20.2 months among patients receiving first-line TKIs, whereas our cohort exhibited a median OS of 3.2 years (32). This difference may reflect variations in patient demographics, smoking patterns, stage distribution, access to subsequent lines of therapy (including later-generation TKIs), and follow-up durations. Similarly, findings from a Swedish study involving 1,419 patients reinforced the prognostic significance of younger age, adenocarcinoma histology, less advanced clinical stage, and fewer comorbidities, mirroring trends observed in our cohort (33). In addition, real-world series of second- and third-generation EGFR-TKIs have likewise highlighted clinical stage, performance status, metastatic burden and EGFR mutation subtype as major determinants of outcome, despite differences in drug potency and resistance profiles (19,34). Taken together, these convergent observations suggest that many of the prognostic patterns identified in our icotinib-treated cohort are not specific to a single agent, but instead reflect broader biological and clinical determinants of outcome in EGFR-mutant NSCLC, even though absolute survival durations differ across TKI generations.

Resistance to EGFR-TKIs remains an inevitable challenge. In our registry, detailed molecular data at the time of acquired resistance (e.g., repeat tissue or plasma genotyping) were not systematically collected, and we could not directly analyze resistance mechanisms in this cohort. Nevertheless, previous studies have shown that the most common mechanisms of resistance to first-generation EGFR-TKIs include emergence of the EGFR T790M gatekeeper mutation, MET amplification, HER2 amplification, and histologic transformation to small-cell lung cancer, among others (35,36). Our findings regarding prognostic factors should therefore be interpreted in the context of first-generation TKI therapy and the typical resistance patterns associated with these agents, while recognizing that the advent of later-generation TKIs has altered subsequent treatment pathways for many patients.

This study has important implications for clinical practice and research. Identifying key prognostic factors allows for the development of pragmatic risk stratification tools to inform patient counseling and follow-up strategies. For instance, patients with non-adenocarcinoma histology or non-sensitizing/unknown EGFR mutations may require closer monitoring or consideration of alternative or intensified regimens. These factors also help refine eligibility criteria and stratification factors for clinical trials, thereby enhancing the comparability of study groups and the reliability of trial outcomes. Beyond clinical applications, our results contribute to the growing understanding of EGFR-mutant cancers, shedding light on tumor growth dynamics and treatment response patterns in a very large, real-world Asian population, which may inform future biomarker-driven drug development.

Despite these strengths, several limitations must be acknowledged. First, missing demographic and clinical data may have introduced bias, particularly in subgroup analyses. Notably, comorbidity information was not captured in a standardized and analyzable format, so we were unable to adjust for comorbid conditions in our multivariable models, and residual confounding by comorbidities may persist. Second, historical heterogeneity and incomplete documentation of EGFR testing reports resulted in a substantial proportion of patients being categorized as having an “unknown mutation type”. This may introduce some imprecision and potential bias; however, our key comparisons and interpretations regarding mutation subtype were confined to the large subgroup with clearly documented exon 19 deletions and L858R mutations, which mitigates the impact of this limitation on our main conclusions. Third, we were unable to capture detailed information on dose adjustments, molecular resistance mechanisms, and post-progression treatments, limiting the comprehensiveness of our analysis across the entire treatment course. Finally, the registry did not systematically collect standardized adverse event or toxicity data; as such, a detailed evaluation of the safety profile of icotinib was beyond the scope of this study. Existing randomized trials and real-world reports have generally shown that EGFR-TKIs have a favorable tolerability profile, particularly when compared with platinum-based chemotherapy in EGFR-mutant NSCLC (37).

Another important consideration is external generalizability. The “Meina Xinsheng” registry was specifically designed around icotinib use at a time when first-generation EGFR-TKIs were the standard targeted therapy in China. As a result, only patients treated with icotinib are included in this dataset. This single-drug design limits the direct extrapolation of our findings to other EGFR-TKIs, particularly second- and third-generation agents. At the same time, it reduces heterogeneity in drug exposure and dosing schedules and thereby strengthens the internal validity of our prognostic analyses under a uniform first-generation TKI regimen. When viewed alongside real-world data for later-generation TKIs, the consistency of key prognostic factors across different EGFR-TKI generations supports the broader relevance of our findings.

Conclusions

In conclusion, this nationwide real-world study provides a comprehensive assessment of survival outcomes and prognostic factors in advanced NSCLC patients treated with icotinib, representing one of the largest analyses of its kind. Female sex, stage III (vs. stage IV) disease, adenocarcinoma histology, EGFR exon 19 deletion, and the use of EGFR-TKI as first-line therapy were independently associated with longer DoT and/or OS, while achieving a CR further improved long-term outcomes. These findings help to identify patients who are more likely to derive durable benefit from EGFR-TKI therapy and support more refined risk stratification and individualized treatment strategies in EGFR-mutant NSCLC.

Acknowledgments

We sincerely thank Lieming Ding, Hena Shi, Jiang Wan, and Yanli Hu from Betta Pharmaceuticals, Hangzhou, China for the coordination.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-275/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-275/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-275/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82373121); the National Key Research and Development Program of China (Nos. 2024ZD0520004, 2024ZD0520000, 2022YFC2505105); the Science and Technology Planning Project of Guangzhou (No. 2024A03J1222); and the R&D Program of Guangzhou National Laboratory (No. SRPG22-017).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-275/coif). W.L. serves as an unpaid Associate Editor-in-Chief of Translational Lung Cancer Research from May 2025 to April 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Guangzhou National Center for Respiratory Medicine (No. ES-2022-197) and was registered at the National Clinical Research Center for Respiratory Disease of China (No. ChNCRCRD-2022-GZ02). All patients provided written consent for their data to be used in scientific analysis at the time of registration.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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